Abstract
BACKGROUND: The ability of unstandardized methods to track kidney growth in clinical trials for autosomal dominant polycystic kidney disease (ADPKD) has not been critically evaluated. METHODS: The Tolvaptan Efficacy and Safety Management of ADPKD and its Outcomes (TEMPO) 3:4 study involved baseline and annual magnetic resonance follow-up imaging yearly for 3 years. Total kidney volume (TKV) measurements were performed on these four time points in addition to the baseline imaging in TEMPO 4:4, initially by Perceptive Informatics (Waltham, MA, USA) using planimetry (original dataset) and for this study by the Mayo Translational PKD Center using semiautomated and complementary automated methods (sequential dataset). In the original dataset, the same reader was assigned to all scans of individual patients in TEMPO 3:4, but readers were reassigned in TEMPO 4:4. Two placebo-treated cohorts were included. In the first (n = 158), intervals between the end of TEMPO 3:4 and the start of TEMPO 4:4 scan visits ranged from 12 to 403 days; in the second (n = 95), the same scan (measured twice) visit was used for both. RESULTS: Growth rates in TEMPO 3:4 were similar in the original and sequential datasets (5.5 and 5.9%/year). Growth rates during the TEMPO 3:4 to TEMPO 4:4 interval were higher in the original (13.7%/year) but were not different in the sequential dataset (4.0%/year). Comparing volumes from the same images, TKVs showed a bias of 2.2% [95% confidence interval (CI) -5.2-9.7] in the original and -0.16% (95% CI -1.91-1.58) in the sequential dataset. CONCLUSIONS: Despite using the same software, TKV and growth rate changes were present, likely due to reader differences in the transition from TEMPO 3:4 to TEMPO 4:4 in the original but not in the sequential dataset. Robust, standardized methods are essential in ADPKD trials to minimize errors in serial TKV measurements.